tbuckley/cabot-search huggingface dataset:
Correction of myocardial changes on an animal experimental model with meldonim
Authors: O Yarmolenko, V Bumeister, O Prykhodko, O Gordienko, N Demikhova
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: None. Prolonged hypoosmolar overhydration causes a volume overload necessitating cardioprotectors together with a complex of measures aimed at stabilizing the water and electrolyte balance. The content of water and electrolytes in the human body changes throughout life, so the body's response to the disorder of water and salt balance may be different depending on age. The fluid overload positively correlates with adverse outcomes in critically ill patients. One of the main tasks of modern cardiology is to find the means of leveling the influence of adverse factors on myocardium in different aged patients. The aim of our study was the determination of morphological changes in the myocardium of old laboratory animals under the influence of severe hypoosmolar hyperhydration and attempt to correct the identified changes by means of meldonium. Materials and methods The experiment was conducted in accordance with the "European Convention of the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes" (Strasbourg, 1986). 18 rats at the age of 22 months were divided into 3 series: 2 experimental and 1 control (6 in each). Animals of the first experimental series were modeling severe hypoosmolar hyperhydration by introduction of 10 ml distilled water three times a day through a tube during 25 days. Animals ate boiled unsalted food and were injected a synthetic analogue of antidiuretic hormone "Minirin" (Ferring) with drinking water 2 times a day at a dose 0.01 mg. In addition, the rats of the second experimental series were injected with meldonium intraperitoneally at a dose of 50 mg/kg once a day throughout the entire experiment. The animals of control series received normal drinking water and food and were injected the "Mynyrin"(Ferring) twice a day at a dose of 0.01 mg, considering the potential effects of vasopressin on the cardiovascular system. We measured the diameter of cardiomyocytes (DCMC) of both ventricles, the relative amount of cardiomyocytes (RACMC), connective tissue (RACT), and vessels (RAV), stromal-parenchymal ratio in the ventricles by the formula (RACT+RAV)/RACMC. Results In myocardium of rats administered meldonium, only isolated stromal hemorrhage are noted, while in myocardial samples of the first experimental series there are numerous hemorrhages. DCMC of left ventricle and DCMC of right ventricle are greater than control at 13.18% (p&amp;lt;0.0001) and 12.27% (p&amp;lt;0.0001) respectively. RAV does not change. RACT of left ventricle and RACT of right ventricle increase respectively by 3.72% (p=0.0060) and 5.23% (p &amp;lt;0.0001). RACMC of right ventricle is smaller than the control parameter by 0.63% (p = 0.0015). Conclusion In old animals, meldonium improves the vascular component of the myocardium. However, we have not found the positive effect of the drug on other studied parameters.
Trend on erectile rehabilitation after radical prostatectomy: Results of an international survey among urologists
Authors: E. Rubilotta, M. Gubbiotti, G.M. Pirola, M. Balzarro, D. Castellani, L. Gemma, J.Y-C. Teoh, A. Polykarpova, A.M. Autrán-Gómez, L. Tortolero Blanco, F. Migliorini, A. Tafuri, A. Antonelli
Journal: European Urology (2022)
A randomized study to compare outcomes of intravesical chemohyperthermia with mitomycin c vs. intravesical BCG for intermediate and high risk Non-Muscle Invasive Bladder Cancer (NMIBC)
Authors: K. Guleria, R. Sood, H. Goel, S. Gahlawat, U. Sharma, A. Singla, P.F. Masood, S. Kabra, R. Singh
Journal: European Urology (2022)
Engineered, fully human nanobody-based CAR T cells have enhanced antitumor activity against hepatocellular carcinoma in preclinical models.
Authors: Aarti Kolluri, Dan Li, Nan Li, Mitchell Ho
Journal: Journal of Clinical Oncology (2022)

e14512 Background: Glypican 3 (GPC3), a cell surface protein associated with early development, is an established biomarker of hepatocellular carcinoma (HCC). In a vast compendium of work, HN3, a human GPC3 nanobody (VH) isolated from a phage library, was shown to abrogate HCC tumors and block the distally located Wnt binding domain of GPC3. To date, it remains challenging how to precisely engineer CAR T cells for improved efficacy in solid tumors. In the context of hepatocellular carcinoma, we determined how hinges and transmembrane portions of varying structures and sizes affect CAR T cell function. Here, we show how rationally designed, engineered Chimeric Antigen Receptor (CAR) T cells containing HN3, demonstrate enhanced CAR T activity in HCC. Methods: We generated and compared multiple permutations of GPC3 targeted CAR T cells containing HN3, CD8, CD28, IgG4 and Fc domains. Incorporation of HN3, into multiple CAR formats yielded nine constructs, which were screened for antigen-specific and antigen-independent signaling using a luciferase reporter system in Hep3B, Huh7 and HepG2 cell lines. For in vivo assessment, immunodeficient NSG mice were intraperitonially injected with Hep3B or Huh7 cells and treated with a single dose (5 or 15 million) of engineered HN3 CAR T cells. Blood was collected at 2, 4 and 5 weeks to assess proliferation, T cell subtypes and exhaustion. Results: In vitro, the HN3-IgG4H-CD28TM CAR T cells induced high specificity and cytotoxic activity. HN3-IgG4H-CD28TM CAR T cells markedly improved HN3 cell killing activity by 30-40% in low (1.6:1) and high (25:1) effector to target ratios. Similarly, in vivo, in a high antigen environment, two determinative changes in the hinge region and transmembrane domains led to complete tumor eradication in immunodeficient mice bearing HCC tumors within 7-10 days. Moreover, HN3-IgG4H-CD28TM CAR T cells maintained specific tumor killing and averted exhaustion by producing a clear T cell response signature of enriched cytotoxic-memory (T emra ) CD8+ along with a subset of naïve T cells. Conclusions: Engineered nanobody based CAR T cells containing the appropriate hinge and transmembrane domains can lead to determinative T cell signaling capable of inducing swift and durable eradication of HCC tumors. Altogether, we show that engineered HN3 CAR T cell therapy demonstrates strong potential for treatment of aggressive HCCs enabled by Wnt dysregulation.
Inguinal lymph node dissection for penile cancer: Results of a minimally invasive approach from a multicenter database
Authors: A. Brassetti, G. Cozzi, P. Gavrilov, J.A. Chavarriaga Soto, A. Bove, U. Anceschi, M.C. Ferriero, R. Mastroianni, L. Misuraca, G. Tuderti, G. Musi, O. De Cobelli, A. Breda, J.M. Gaya Sopena, D. Camacho, R. Varela, G. Simone
Journal: European Urology (2022)
Individual variability in brain representations of pain
Authors: Lada Kohoutová, Lauren Y. Atlas, Christian Büchel, Jason T. Buhle, Stephan Geuter, Marieke Jepma, Leonie Koban, Anjali Krishnan, Dong Hee Lee, Sungwoo Lee, Mathieu Roy, Scott M. Schafer, Liane Schmidt, Tor D. Wager, Choong-Wan Woo
Journal: Nature Neuroscience (2022)
Association of stress-related disorders with subsequent risk of all-cause and cause-specific mortality: A population-based and sibling-controlled cohort study
Authors: Fan Tian, Qing Shen, Yihan Hu, Weimin Ye, Unnur A. Valdimarsdóttir, Huan Song, Fang Fang
Journal: The Lancet Regional Health - Europe (2022)

Prior research provides suggestive evidence on an association between stress-related disorders and mortality. No previous study has however addressed the role of familial confounding on such association.We conducted a nationwide cohort study of 189,757 individuals with a first-onset stress-related disorder between January 1, 1981 and December 31, 2016 in Sweden (i.e., exposed patients), 1,896,352 matched unexposed individuals, and 207,479 unaffected full siblings of the exposed patients. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause and cause-specific mortality.During a mean follow-up of 9.42 years, an elevated risk of all-cause mortality was observed during the entire follow-up among patients with stress-related disorders, compared with either unexposed individuals or their unaffected full siblings. Such excess risk was most pronounced within the first year after diagnosis of stress-related disorders (HR, 3.19 [95% CI, 2.87-3.54] in population-based comparison; HR, 3.21 [95% CI, 2.56-4.02] in sibling-based comparison). The excess risk decreased but remained statistically significant thereafter (HR, 1.64 [95% CI, 1.60-1.67] in population-based comparison; HR, 1.61 [95% CI, 1.54-1.68] in sibling-based comparison). An increased risk was observed for almost all cause-specific mortality, with greater risk increase for deaths from unnatural causes, especially suicide, and potentially avoidable causes.Stress-related disorders were associated with an increased risk of all-cause mortality and multiple cause-specific mortality, and the risk elevation was independent of familial confounding. The excess mortality attributable to unnatural causes and potentially avoidable causes highlights the importance of clinical surveillance of major health hazards among patients with stress-related disorders.EU Horizon 2020 Research and Innovation Action Grant, 1.3.5 Project for Disciplines of Excellence at West China Hospital of Sichuan University, National Natural Science Foundation of China, Icelandic Research Fund (Grant of Excellence), ERC Consolidator Grant, and Swedish Research Council.
Fixed-duration (FD) ibrutinib (I) + venetoclax (V) for first-line (1L) treatment (tx) of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Three-year follow-up from the FD cohort of the phase 2 CAPTIVATE study.
Authors: William G. Wierda, Paul M. Barr, Tanya Siddiqi, John N. Allan, Thomas J. Kipps, Livio Trentin, Ryan Jacobs, Sharon Jackson, Alessandra Tedeschi, Stephen Opat, Rajat Bannerji, Bryone J. Kuss, Carol Moreno, Lisa J. Croner, Edith Szafer-Glusman, Cathy Zhou, Anita Szoke, James P. Dean, Paolo Ghia, Constantine Si Lun Tam
Journal: Journal of Clinical Oncology (2022)

7519 Background: CAPTIVATE (PCYC-1142) is a multicenter phase 2 study of 1L I+V in CLL. The primary analysis (PA) evaluating FD tx with I+V was previously presented (Ghia et al., ASCO 2021). Here we present 3-y follow-up results from the FD cohort. Methods: Patients (pts) aged ≤70 y with previously untreated CLL/SLL received 3 cycles of I then 12 cycles of I+V (I 420 mg/d orally; V ramp-up to 400 mg/d orally). Responses were investigator assessed per iwCLL 2008 criteria. Undetectable minimal residual disease (uMRD; &lt;10 -4 ) was measured by 8-color flow cytometry. Serious AEs (SAEs) deemed related to I reported &gt;30 d after last dose of study drug were collected. Results: 159 pts were enrolled (median age 60 y), including pts with high-risk features of del(17p)/ TP53 mutation (17%), unmutated IGHV (uIGHV; 56%), and complex karyotype (19%). 147 (92%) and 149 (94%) pts completed tx with I and V, respectively. With 1 y of additional follow-up since PA, median time on study was 39 mo (range 1-41). ORR was 96% and was consistent (96%-97%) in pts with high-risk features (Table).The primary endpoint of complete response (CR) including CR with incomplete bone marrow recovery (CRi) rate in pts without del(17p) (n=136) increased nominally from 56% (95% CI, 48-64) to 58% (95% CI 50-66); in all pts, CR rate increased from 55% (95% CI 48-63) to 57% (95% CI 50-65). In pts achieving CR, 93% had durable responses lasting ≥12 mo post-tx. Of pts with uMRD in peripheral blood at 3 mo post-tx, 66/85 (78%) evaluable pts maintained uMRD through 12-mo post-tx. At 36 mo, PFS was 88% (95% CI 82‒92) and OS was 98% (95% CI 94‒99); similar rates were seen in pts with high-risk features (Table). All pts are off tx; no new SAEs of any kind have occurred since the PA. Available data on relevant mutations in BTK, PLCɣ2, or BCL-2 at time of PD will be presented. As of January 2022, 12 pts were retreated with single-agent I after PD (tx duration range 3-29 mo); of evaluated pts, 7/9 had partial responses and 2/9 had stable disease. Conclusions: Fixed duration I+V continues to provide deep, durable responses and clinically meaningful PFS, including in pts with high-risk disease features, representing an all-oral, once-daily, chemotherapy-free FD regimen for previously untreated pts with CLL/SLL. With an additional 1 y of follow-up, no OS events or SAEs occurred. Manageable safety profile is unchanged as previously reported. To date, successful single-agent I retreatment responses are observed. Clinical trial information: NCT02910583. [Table: see text]
Financial impact of generic therapeutic interchange of abiraterone in the oncology care model for the U.S. Oncology Network.
Authors: Puneeth Indurlal, Hope Ives, Jody S. Garey, Margaret McGuinness, Alonso Victor Pacheco, Lalan S. Wilfong
Journal: Journal of Clinical Oncology (2022)

e17019 Background: Therapeutic interchange (TIC) to lower-cost generic products offers significant cost savings to payers and patients while maintaining equivalent quality of care. The Oncology Care Model (OCM) is a value-based care program from Medicare that rewards practices for decreasing the total cost of care (TCOC) compared to historical baseline prices that are adjusted by a trend factor to account for rising cost trends in oncology. One strategy for bending the cost curve is to utilize lower cost medications. A generic version of abiraterone acetate (FDA approved for treatment of Prostate Cancer) was first introduced into the market in late 2018. This led to a concerted approach to interchange the brand product with the generic equivalent in The US Oncology Network (The Network) as an opportunity to reduce TCOC. Here we describe utilization and the financial impact of abiraterone TIC in The Network during OCM performance period 8 (PP8) which enrolled patients from 1/2/2020 to 7/1/2020. Methods: Prescription drugs dispense data for the 14 US Oncology Network practices participating in the OCM were used to determine brand and generic abiraterone utilization. The impact of TIC on TCOC was measured by comparing the cost of the generic product vs. the estimated cost of the brand agents. Results: TIC resulted in an increase in generic abiraterone use from prior performance periods. Generic abiraterone increased from 0% in PP4 to 24% in PP5, 55% in PP6, 67% in PP7 and 80% in PP8 within the Network. We compared the actual cost of all abiraterone dispenses in PP8 vs. the calculated cost (based on Average Wholesale Price less 17.5%) of the brand product if the more expensive brand drugs were used instead. The difference in the actual cost vs estimated cost led to a savings of $4.37 million in PP6, $6.34 million in PP7 and $9.37 million in PP8 (about 1% of TCOC) by using generic versus brand abiraterone alone. Conclusions: TIC from brand to generic abiraterone in The Network generated significant savings for OCM. Continued shift towards lower cost generics will increase savings to CMS in the Oncology Care Model. We estimate that 100% Network adoption of the generic abiraterone could save nearly 1.25% of the TCOC compared to continued use of brand product.
Recombinant human adenovirus 5 injection plus toripalimab therapy in patients with advanced and refractory melanoma: A single arm, single-center, prospective study.
Authors: Huaxin Zhao, Xianling Guo, Zhuqing Liu, Qing Xu
Journal: Journal of Clinical Oncology (2022)

e21503 Background: Treatment options are limited for patients with advanced melanoma and refractory melenoma, especially for acral and mucosal melanoma. Previous data showed that the objective response rate (ORR) of second-line PD1 monotherapy for acral and mucosal melanoma were 14-15.8% and 0-13.3%, respectively. We evaluate the safety and efficacy of recombinant human adenovirus 5 injection (oncolytic virus) plus toripalimab (PD-1 antibody) for patients who have progressed on checkpoint inhibitors, chemotherapy and anti-angiogenesis. Preliminary analysis of efficacy- related factors. Methods: Patients received the recombinant human adenovirus 5 injection (2ml) local lesions plus toripalimab 240mg systemic therapy every 2 weeks until progression or intolerable toxicity. The primary objective was safety and ORR. Secondary objective included progression-free survival (PFS) and disease control rate (DCR). Efficacy assessments were performed every 2 months according to RECIST v1.1 criteria. Blood samples were collected from patients prospectively. Serum interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, Tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) were measured at baseline and after two cycles of treatment via flow cytometry. The peripheral blood neutrophils and lymphocytes were collected simultaneously. Results: Ten cases of patients were enrolled from November 2020 to January 2022. Baseline character:primary site (1 cutaneous melanoma; 5 acral melanoma; 4 mucosal melanoma), prior therapy (anti-PD1 100%; anti-angiogenesis 60%; chemotherapy 60%; second line and above 40%), 50% liver/bone lesions. All patients evaluated received at least 2 cycles of the combination regimen. The treatment-related adverse event was fever, accounting for 80%, and there were no other adverse events. The ORR was 20% (2PR) and the DCR was 70% (2PR, 5SD, 3PD). The 2-month PFS was 70%, and the median PFS has not yet been reached. Disease progression in 3 patients including liver and bone lesion. Higher baseline lymphocyte levels and lower neutrophil-to-lymphocyte ratio (NLR) values were found in the respongders compared with non-responders. The serum IL-6, IL-8, IL-10, and TNF-α levels were significantly increased in the responders after 2 cycles of treatment. Conclusions: The preliminary data showed that the combination of recombinant human adenovirus 5 injection plus toripalimab demonstrated acceptable toxicity and promising antitumor efficacy in patients with advanced and refractory melanoma, and promoted favorable changes in serum IL-6, IL-8, IL-10 and TNF-α levels in clinical responders. High baseline lymphocyte and low NLR values may be predictors of treatment response. Long-term survival data remain to continue with follow-up. It is worth to further validate the efficacy in a randomized prospective trial. Clinical trial information: 2000033959.
The SNAP Cycle and Diabetes Management During a One-Time Change in Disbursement Schedule
Authors: Sabrina K. Young, Alicia Atwood, Lindsay Allen, Nathan Pauly
Journal: Diabetes Care (2022)

OBJECTIVE The 2018–2019 federal government partial shutdown resulted in a one-time disruption to the usual disbursement schedule of Supplemental Nutrition Assistance Program (SNAP) benefits nationwide. We assessed the relationship between this disruption and hyperglycemia and hypoglycemia medical encounters among beneficiaries with diabetes. RESEARCH DESIGN AND METHODS To estimate whether the one-time change in benefit disbursement affected the monthly cycle of hyperglycemia or hypoglycemia encounter rates, we used linked administrative Medicaid claims and SNAP disbursement data from West Virginia in a fixed-effects model with interactions between week of the month and the two months of interest—January and February 2019. We controlled for week, month, year, and county effects as well as individual characteristics, and we clustered SEs by individual. RESULTS We found that the early disbursement of SNAP benefits in January 2019 resulted in a spike in hyperglycemia four times the rate in a typical month. Further, we found a decrease in both hyperglycemia and hypoglycemia in late February. CONCLUSIONS Our findings suggest that the early distribution of benefits led to a temporary increase in food consumption among West Virginia Medicaid beneficiaries with diabetes. Findings from late February also imply that individuals may have a way to prepare for reduced food resources. These results shed new light on the effects of unexpected changes to the timing of safety net payments as well as an understanding of unintended consequences of government shutdowns.
MEK-inhibitor (inh) and hydroxychloroquine (HCQ) in <i>KRAS</i>-mutated advanced pancreatic ductal adenocarcinoma (PDAC).
Authors: Maahum Mehdi, Samih Z Thalji, Aditya V. Shreenivas, Sakti Chakrabarti, James P. Thomas, Kathleen K. Christians, Douglas B. Evans, William A. Hall, Beth Erickson, Bicky Thapa, Gulrayz Ahmed, Omid Yazdanpanah, Razelle Kurzrock, Mohammed Aldakkak, Mary Beth Holden, Ben George, Susan Tsai, Carolyn Oxencis, Thomas McFall, Mandana Kamgar
Journal: Journal of Clinical Oncology (2022)

e16260 Background: Therapeutic inhibition of constitutive signaling mediated by mutated KRAS in PDAC remains a challenge except for modest success reported with KRAS G12C inhibition. A combinatorial strategy utilizing simultaneous MEK and autophagy inhibition holds therapeutic promise based on mechanism of action and preclinical data. We described characteristics and outcomes of patients (pts) treated with MEK-inh and HCQ at our institution. Methods: Ten KRAS-mutated advanced PDAC pts were treated with trametinib-HCQ (n = 9) or cobimetinib-HCQ (n = 1) off label due to lack of standard treatment options or toxicity concerns with cytotoxic systemic therapy. Trametinib dose was 2 mg once daily orally, Cobimetinib dose was 20 mg BID orally for 3/4 weeks cycles. HCQ was started at 200 mg BID and up-titrated weekly to 600 mg BID. Description of baseline and treatment (tx) characteristics, safety and efficacy is provided. Results: Median age at diagnosis was 61.3 years, and 7 pts were female. The number of prior lines of tx were 0/1/2/3/4 in 3/2/1/2/2 pts, respectively. KRAS mutations were: G12R/G12D/G12V/Q61H in 6/2/1/1 pts. Median overall survival was 6.6 months (m) in all pts, and 6.6/1.7 m in KRAS G12R/other KRAS (p = 0.31). Median progression-free survival was 5.7/6.2/1.5 m in all/ KRAS G12R/other KRAS (p = 0.16). Among 8 pts with evaluable response, 1 (12%) had partial response ( KRAS G12R) and 4 (50%) stable disease (3/4 KRAS G12R) as best response with disease control rate of 63%/80%/33% in total/ KRAS G12R/other KRAS (p = 0.29). Toxicity data are summarized in table 1. Conclusions: MEK-inh-HCQ demonstrated modest efficacy and manageable toxicities among KRAS G12R PDAC pts. Unlike G12D and G12V mutations in the KRAS gene, G12R is defective of conductive interactions for both PI3Ka and NF1. This ultimately results in a weakened signal being shunted through MAPK cascade and provides a unique opportunity where MEK inh can ablate signaling without the alternate pathways and WT-RAS isoforms compensating. Furthermore, as activation of PI3Ka is known to suppress autophagy, its lack of activation by KRAS G12R further sensitizes cells to HCQ. The combination therapy MEK-inh-HCQ is therefore mechanistically-rationale and warrants the further investigation of KRAS G12R as an actionable biomarker.[Table: see text]